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MCW - Pharmacology > Block 2_2 - Histamine > Flashcards

Block 2_2 - Histamine Flashcards

1
Q

Describe synthesis of Histamine

  • cofactors?
A

Histidine —Histadine Decarboxylase—-> Histamine

(essential amino acid L-histidine)

  • histidine decarboxylase uses pyridoxal-5-phosphate as cofactor
  • inhibited by methyl-histidine
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2
Q

Name the 2 histamine degrading enzymes

A

Diamine oxidase (DAO)

Histamine-N-methyl transferase (HNMT)

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3
Q

Histamine General Uses (3)

A
  1. Mediator of immediate allergic and inflammatory reactions
  2. role in gastric acid secretion
  3. neurotransmitter and neuromodulator
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4
Q

Highest source of Histamine

A

ubiquitous

  • lung, skin and stomach
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5
Q

Localization of Histamine

“Pools” of Histamine located where?

A
  1. In tissues - mast cells
  2. In blood - Basophils
  3. Non-mast cells (gastric mucosa cells, epidermis, neurons)
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6
Q

Histamine in Tissues (mast cells) and Blood (basophils)

  1. Synthesized and stored?
  2. Turnover?
A
  1. synthesized and stored in secretory granules in an inactive form; bound to a proteoglycan
    - herpain-sulfate and ATP: mast cells
    - chondroitin-sulfate: basophils
  2. Slow turnover in mast cells
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7
Q

Histamine in non-mast cells

  1. Synthesis and storage? Turnover?
  2. levels of histamine
A
  1. no granules, continuously synthesized and releeased, rapid turnover
  2. correlate with activity of histidine decarboxylase (inducible enzyme)
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8
Q

Release of Histamine - Antigen-Antibody Reaction

2 steps?

a) ___ dependent
b) releases other _____ as well

A
  1. Induction of IgE-mediated allergic sensitivity to drugs and other allergens
    - IgE antibody produced and fixed to mast cells and blood basophils
  2. Response of IgE-sensitized cells to subsequent exposure to allergens.
    a) Ca2+
    b) mediators
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9
Q
  1. Effect of Histamine Release (or after injection) within seconds
  2. within minutes
A
  1. experience burning, itching sensation, most marked in palms of hand, in the face, scalp, and ears followed by intense warmth. Skin reddens, blood pressure falls, HR increases, headaches are common
  2. BP recovers and hives will appear on skin
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10
Q

Drugs, Peptides, Venoms that promote the release of histamine

  1. Antigen-antibody mediated release?
  2. Direct or Indirect Stimulation?
  3. Drug Examples
  4. Peptide Examples
  5. Venom Examples
  6. Mechanism of action
A
  1. No
  2. Direct Stimulation without prior exposure (CLINICAL CONCERN)
  3. Succinylcholine, morphine, curare, certain carbohydrate plasma expanders (dextran, PVP), some antibiotics (Vancomycin-induced “red-man syndrome”)
  4. Substance P; complement (C3a, C5a)
  5. wasp venom
  6. increase intracellular Ca2+ via a number of different pathways
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11
Q

Red-man (red neck, red person) Syndrome

1a-c. Cause

  1. Seen following?
  2. Physical Presentation
  3. Physiologic Effect
A

1a. Vancomycin
- Gram-positive bacteria
- last resort antibiotic
- serious gram positive infections
1b. Mast cell degranulation (not allergic reaction to vancomycin)
1c. altered histamine metabolism
2. Following rapid IV infusion
3. Rash in face, neck, upper torso
4. Hypotension

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12
Q

Other stimuli that release histamine (4)

A
  1. Cold urticaria (hives)
  2. Cholinergic urticaria
    - increased sympathetic nervous activity (seen with exercise, stress) stimulates cholinergic fibers innervating sweat glands to release Ach, leading to mast cell degranulation
  3. Solar urticaria
  4. nonspecific cell damage
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13
Q

Agents which INHIBIT the release of histamine (6)

A
  1. Cromolyn sodium
  2. Omalizumab
  3. ß-adrenoreceptor agonists
  4. Methylxanthines
  5. Corticosteroids used for asthma treatment
  6. Histamine inhibits its own release
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14
Q

**Cromolyn sodium **

  1. Mechanism of action
  2. Route of Admin
  3. Use
  4. Side Effects
A
  1. Stabilizes mast cell membrane to prevent release of histamine
  • no mast cell degranulation
  • exact cellular/molecular mechanism is not clear
  1. Inhalation (mainly)
    - others: oral, nasal, ophthalmic
  2. inhaled anti-inflammatory agent
  • preventive management of asthma (chronic control)
  • prophylaxis of bronchospasm (allergen- or exercise-induced)
  • Not a rescue medicine!
  • allergies, allergic rhinitis (Nasal formulation)
  • conjunctivitis (Ophthalmic formulation)
  • Systemic mastocytosis (oral formulation)
  • Off-label uses for food allergy an irritable bowel syndrome (IBS)
  1. Safe drug with few side effects
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15
Q

Omalizumab

  1. Mechanism of action
  2. Route of Admin
  3. Use
  4. Side Effects
A

Monoclonal antibody

  1. Decreases amount of antigen specific IgE that normally binds to and sensitizes mast cells
  • “anti-antibody antibody” - monospecific anti-IgE antibody
  • an IgG antibody for which the antigen is the Fc Region of the IgE antibody
  • binds tightly to free IgE in the circulation to form omalizumab-IgE complexes
  • so no affinity for the FcRI (receptor for Fc)
  1. Subcutaneous administration (2-4 weeks)
  2. moderate to severe, persistent allergic asthma not adequately controlled with inhaled corticosteroids
    * used as a last resort drug
  3. life threatening anaphylaxis
    - bleeding-related adverse effects
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16
Q

ß Adrenoreceptor agonists - Mechanism of action

A

stimulate adenylyl cyclase which increases cAMP

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17
Q

Methylxanthines - mechanism of action

A

phosphodiesterase inhibitors, block metabolism of cAMP

18
Q

Histamine H1 Receptor

  1. G protein?
  2. Distribution
  3. Representative antagonist
A
  1. Gq (↑ Ca2+; ↑ NO and ↑cGMP)
  2. smooth muscle, endothelial cells, CNS
  3. Chlorpheniramine
19
Q

Histamine H2 Receptor

  1. G protein
  2. Distribution
  3. Representative antagonist
A
  1. Gs (↑ cAMP)
  2. Gastric parietal cells, cardiac muscle, mast cells, CNS
  3. Ranitidine
20
Q

Histamine Effects (6)

A
  1. Cardiovascular
  2. Other non-vascular (extravascular) smooth muscle
  3. exocrine glands
  4. peripheral nerve endings
  5. “Triple Response of Lewis”
  6. Neuroendocrine Effects
21
Q

Histamine - Cardiovascular Effects (5)

A
  1. Vasodilation - most important vascular effect in humans
  • H1 (endothelial cells) - ↑ Ca2+ intracellular and activation of nitric oxide synthase
    • (NO is a vasodilator in vascular smooth muscle)
  • H2 (vascular smooth muscle cells) - coupled to increase in cAMP
    • ↓ intracellular Ca2+
    • ↓ rate of myosin phosphorylation
  1. ↓ Blood Pressure
  • H1 and H2 receptors
  • dilates resistance vessels
  1. vasoconstriction of large vessels
  • H1 receptors located on vascular smooth muscle cells
  • increase in intracellular Ca2+
  1. Increased vascular permeability
  • H1 receptor
  • located on postcapillary venules on endothelial cells
  • Increase in calcium causes the endothelial cells to contract and expose basement membrane which is freely permeable to plasma protein and fluid
  1. Heart - Increased contractility and electrical conduction
    * Predominantly H2 receptors (cardiac myocytes)
22
Q

Histamine Receptor Activation: Other non-vascular (extravascular) smooth muscle

A
  1. bronchioles
  • H1: contraction
  • H2: relaxation (minor)
  • effects are more pronounced in asthma/other pulmonary diseases
    2. intestinal smooth muscle
  • H1: contraction
23
Q

Histamine Receptor Activation: Exocrine Glands

A

GI secretory tissue (parietal cell)

  • H2 - gastric acid secretion
  • target for H2 antagonists
24
Q

Histamine Receptor Activation: peripheral nerve endings

A

H1 - pain & itching

25
Q

Triple Response of Lewis

A

Flush, Flare, Wheal

•  Flush (red line)

  • H1-dilation
  •   a red dot on the skin following a mosquito bite

•  Flare

  • axonal reflex mediated by H1 receptors
  • histamine stimulates sensory nerve endings and causes vasodilation
  •   a big red patch

•  Wheal

- H1

  • increase in vascular permeability (local edema)
  • a big bump due to leaky capillaries
26
Q

Neuroendocrine (Central Effects) of Histamine (5)

A

•  Increase arousal/wakefullness
– H1

•  Decrease appetite
– H1

•  Cardiovascular regulation
– H1& H2

•  Thermoregulation
– H1& H2

•  Pain perception
– H1& H2

27
Q

First Generation H1 Receptor Blockers (antihistamines)

A
  1. Diphenhydramine
  2. Dimenhydrinate
  3. Chlorpheniramine
  4. Promethazine
28
Q

Second Generation (Nonsedating) H1 Receptor Blockers

  • side effects?
A
  1. Fexofenadine
  2. Loratadine
  3. Desloratadine
  4. Cetirizine

second generation drugs have little to no anticholinergic side-effects, do not cross BBB to CNS

29
Q

Pharmacology - H1 Receptor Antagonists

  1. antagonist type
  2. first generation effects?
  3. second generation effects?
A
  1. specific reversible competitive antagonists of the H1 receptors located in both periphery and brain
    * Inverse agonist because it reduces constitutive activity of the receptor and compete with histamine
  2. first generation drugs have other non-specific effects unrelated to H1 receptor blockade
  3. second generation have little or no CNS effects
30
Q

Major Pharmacologic Effect of H1 Antagonists

  1. General
  2. Capillary permeability
  3. Immediate Hypersensitivity Reactions
  4. CNS
  5. Peripheral and central anticholinergic effect
  6. Local anesthetic effect
A
  1. Reduce symptoms associated with allergic responses/inflammation
    * Histamine released during allergic reaction causes blood vessels to dilate/also causing redness, swelling, itching and changes in the secretions of nasal tissue, (i.e. vascular permeability).
  2. inhibited
  3. anaphylaxis and allergy
  • Suppress itching and edema
  • no effect on hypotension or bronchoconstriction
  1. First generation both stimulate and depress the CNS
  • CNS stimulation seen with overdose (more common in children)
  • CNS depression is more commonly seen in sedation, slowed reaction times, decreased alertness
  • some 1st generation prevent motion sickness via CNS anti-cholinergic effect
  1. Seen with many 1st generation drugs
  • atropine-like effect (inhibit responses to Ach via blockage of muscarinic receptors) - think about anticholinergic syndrome
  • dry mucus membranes
  • urinary retention
  1. seen with some 1st generation drugs at high dose (e.g. promethazine)
31
Q

Pharmacokinetics of H1 Receptor Blockers

  1. Route of Admin
  2. Distribution - Which generation of antihistamines are less likely to enter the brain?
  3. Metabolism
A
  1. Oral administration (rapid absorption)
    - topical (skin or ocular) and nasal preparations also available
  2. 2nd generation
  3. Extensive Liver metabolism
  • 2nd generation - some are metabolized by P450 Enzymes (CYP3A4/CYP2D6)
  • active metabolites
    • Terfenadine is metabolized to fexofenadine
    • Loratadine is metabolized to (descarboethoxyloratadine) desloratadine
    • Cetirizine is active metabolite of hydroxyzine
32
Q

H1 Receptor Blockers Toxicity/Major Side Effects (4)

A
  1. Sedation - CNS effects are the msot common side effects seen with first generation

Mechanism: inhibition of BOTH cholinergic and histaminergic (H1) pathways in CNS

  • 1st gen - elicit paradoxical CNS stimulation in children

2nd generation drugs claim to have no sedative effect (cetirizine has the most sedative effect)

  1. GI side effects (more minor)

•  Loss of appetite, nausea, vomiting

  1. Other anti-muscarinic (anticholinergic) side effects (1st gen only)
    * Dry mouth, dryness of respiratory passages
  2. Cardiovascular toxicity
33
Q

Cardiac Toxicity of Loratadine

A

Metabolized by P450 Enzymes (CYP3A4 and 2D6) to desloratadine

  • no cardiac toxicity associated with this drug
34
Q

H1 Receptor Blockers - Therapeutic Uses (name drug for each use) (5)

A
  1. Acute Allergies (less effective for seasonal allergies)
  • 1st Generation
    • diphenhydramine (most sedative effect of 1st gen drugs)
    • Chlorpheniramine (most potent, less prone to cause drowsiness)
  • 2nd generation - all drugs
    • Loratadine
    • desloratadine
    • fesofenadine
    • cetirizine (most sedative effect of 2nd gen)
  1. Motion sickness - due to anticholinergic effects
  • dimenhydrinate
  • promethazine
  • **diphenhydramine **

note: scopolamine - muscarinic receptor antagonist typically used to treat motion sickness
3. Diphenhydramine

  • Non-prescription sleeping tablets
  • early stage Parkinson’s disease
  1. dimenhydrinate - Vestibular Disturbances
  2. **promethazine - **Chemotherapy-induced nausea/vomiting
35
Q

H2 Receptor Antagonists - name drugs

  • general use
A

Cimetidine

Ranitidine

Famotidine

  • relief of symptoms of gastric upset/peptic ulcer disease (gastroesophaeal reflux disease)
36
Q

H2 Receptor - Physiology

A
  •   Histamine released from mast cells and enterochromaffin-like cells
  •   Release is stimulated by vagus nerve and gastrin
  •   Histamine acts on H2 receptors on parietal cells

–  Increase adenyl cyclase, cAMP, PKA
–  Increase in Acid (H+)

•  Ach and gastrin also have direct effect on parietal cells to release acid

37
Q

H2 Receptor Antagonists - Pharmacology

A

1.  Reversible competitive inhibitors

–  specific for H2 receptors on basolateral membrane of parietal cells
–  Act as inverse agonists

  1. inhibit basal (fasting) gastric acid secretion

•  inhibit nocturnal gastric acid secretion

–  big determinant in healing of ulcers

  1.   Reduce volume of gastric acid and H+ concentration
38
Q

H2 Receptor Antagonists - Pharmacokinetics

  1. Route of Admin
  2. Metabolism
  3. Excretion
A
  1. oral administration - rapidly absorbed
  2. small amount undergo liver metabolism
  3. parent drug & metabolites: excreted by kidneys
39
Q

H2 Receptor Antagonists - Side Effects (3)

A
  1. low incidence of side effects, usually minor (exception: cimetidine)
    - include diarrhea, headache, drowsiness
  2. less common include CNS effects: confusion, delirium, slurred speech (happens primarily with IV use or in elderly patients
  3. any drug that inhibit gastric acid secretion can alter bioavailability of other drugs
40
Q

Cimetidine Side Effects

A

•  Cimetidine inhibits P450 metabolism

–  ranitidine also inhibits P450 metabolism (much lesser extent)

–  prolongs half-life of other drugs that are substrates for P450 metabolism

  • Effect of Long term use at high doses:
    • decreases testosterone binding and inhibits a CYP enzyme that hydroxylates estradiol
    • in men: gynecomastia (breast enalrgement), reduced sperm count, impotence
41
Q

H2 Receptor Antagonists - Therapeutic Uses (4)

A
  1. Major Use: Treat uncomplicated gastroesophageal reflux (GERD)
  2. promote healing of gastric and duodenal ulcers
  3. prevent occurence of stress ulcers
  4. Zollinger-Ellison Syndrome - pancreas tumor overproducing gastrin (historically cimetidine H2 antagonist used)
    * preferred treatment today is proton pump inhibitor
42
Q

Potency of H2 antagonists

A

Famotidine > Nizatidine = Ranitidine > Cimetidine

MCW - Pharmacology (8 decks)

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